Quaternary ammonium compounds

ABSTRACT

The compound 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(trifluoromethyl) phenol may be used to prepare the compound (3R)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium bromide by reaction with methyl bromide.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/348 930, filed 26 Oct. 2001, U.S. Provisional PatentApplication No. 60/361 979, filed 6 Mar. 2002, and U.S. ProvisionalPatent Application No. 60/391 521, filed 25 Jun. 2002, and the entiredisclosures of which are herein incorporated by reference.

TECHNICAL FIELD

The present invention concerns a novel class of quaternary ammoniumcompounds, pharmaceutical compositions containing the same, thecompounds for use as medicaments, and use of the compounds for themanufacture of specific medicaments. The present invention also concernsa method of treatment involving administration of the compounds.

The novel compounds are useful as antimuscarinic agents. In particular,the novel compounds are useful for the treatment of asthma, a group ofbreathing disorders termed Chronic Obstructive Pulmonary Disease (COPD),allergic rhinitis, and rhinorrhea due to the common cold.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,382,600 discloses (substituted) 3,3-diphenylpropylaminesuseful for treating urinary incontinence. In particular, it discloses2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol, also knownas N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine,with the generic name of tolterodine, as being useful to treat urinaryincontinence. Tolterodine is the compound of Example 22 of U.S. Pat. No.5,382,600.

It is preferred that tolterodine is prepared by the processes ofInternational Publication W098/29402 (U.S. Pat. No. 5,922,914).

H Postlind et al, Drug Metabolism and Disposition, 26(4): 289-293 (1998)discloses that tolterodine is a muscarinic receptor antagonist. It ispresently being sold in a number of different countries for treatment ofurinary incontinence under the name Detrol®, marketed by Pharmacia. Whentolterodine is used to treat urinary incontinence it is administeredperorally as a tablet. The major, active metabolite of tolterodine isthe 5-hydroxymethyl derivative of tolterodine.

U.S. Pat. No. 5,559,269 and H Postlind et al, Drug Metabolism andDisposition, 26(4): 289-293 (1998) disclose hydroxytolterodine. U.S.Pat. No. 5,559,269 discloses this compound as being useful to treaturinary incontinence. Pharmacol. Toxicol., 81: 169-172 (1997) disclosesthat hydroxytolterodine has antimuscarinic activity.

The international patent application W098/43942 disclosestherapeutically active diarylpropylamines, which have favorableanticholinergic properties, and which can be used for the treatment ofdisorders related to urinary incontinence.

WO 02/34245 discloses the use of tolterodine for treating asthma, COPD,and allergic rhinitis.

The currently marketed administration form of tolterodine is film-coatedtablets containing 1 mg or 2 mg of tolterodine L-tartrate, or extendedrelease capsules containing 2 mg or 4 mg of tolterodine L-tartrate forrelease in the gastrointestinal tract. Consumers constantly requirealternative delivery forms with favorable efficacy and/or which simplifythe treatment, thus improving their quality of life.

Atropine methonitrate and ipratropium are quaternary ammoniumderivatives of atropine. Ipratropium bromide is used by inhalation toproduce bronchodilation. Ipratropium is 8-isopropylnoratropinemethobromide and is disclosed in U.S. Pat. No. 3,505,337.

Yono M et al, European Journal of Pharmacology (1999) 368:223-230, isconcerned with the pharmacological effects of tolterodine, anantimuscarinic drug, in isolated human urinary bladder smooth muscle.

Ruffmann R et al, The Journal of International Medical Research (1998)16:317-330, reviews use of flavoxate hydrochloride or alternativecompounds, such as terodiline hydrochloride and emepronium bromide, inthe treatment of urge incontinence.

Stewart B H et al, The Journal of Urology (1976) 115:558-559 disclosestherapy of mild to moderate stress urinary incontinence with acombination of phenylpropanolamine hydrochloride, chlorpheniraminemaleate, and isopropamide iodide in a sustained release capsule.

WO 95/10269 and WO 95/10270 disclose the use of R-and S-terodiline,respectively, as drugs for treating conditions related to the compounds'activities as anticholinergic agents.

Despite the above advances in the art, it is desirable to develop novelpharmaceutical compounds that further improve the quality of life for alarge number of individuals.

SUMMARY OF THE INVENTION

For these and other purposes, it is an object of the present inventionto provide highly efficient pharmaceutical compounds for treatment ofasthma.

It is also an object of the present invention to provide highlyefficient pharmaceutical compounds for treatment of Chronic ObstructivePulmonary Disease (COPD).

It is a further object of the present invention to provide highlyefficient pharmaceutical compounds for treatment of allergic rhinitis.

It is an object of the present invention to provide highly efficientpharmaceutical compounds for treatment of rhinorrhea due to the commoncold.

It is also an object of the present invention to providepharmaceutically effective 3,3-diphenylpropylamine derivatives having anincreased residence time in lung upon pulmonary administration.

It is an object of the present invention to provide a novel class of3,3-diphenylpropylamine derivatives having favorable properties.

For these and other objects that will be evident from the followingdisclosure, the present invention provides a quaternary ammoniumcompound of the formula

and any stereoisomers thereof, wherein

R₁, R₂ and R₃ independently represent C₁-C₆ alkyl, optionallysubstituted with phenyl or hydroxyl, or both, and wherein any two of R₁,R₂ and R₃ may form a ring together with the quaternary ammoniumnitrogen;

R₄ represents

-   -   —H,    -   —CH₃, or    -   —CO—R₄₋₁ wherein R₄₋₁ represents        -   —(C₁-C₄ alkyl),        -   —(C₁-C₄ alkoxy), or        -   —NR₄₋₂R_(4-3,) wherein R₄₋₂ and R₄₋₃            independently represent —H or —(C₁-C₄ alkyl), and

R₅, R₆ and R₇ independently represent

-   -   —H,    -   —OCH₃,    -   —OH,    -   —CONH₂,    -   —SO₂NH₂,    -   —F, —Cl, —Br, —I,    -   —CF₃, or    -   —(C₁-C₄ alkyl), optionally substituted with one        or two        -   —OH,        -   —(C₁-C₄ alkoxy),        -   —COOH, or        -   —CO—O—(C₁-C₃ alkyl), and

X⁻ represents an anion of a pharmaceutically acceptable acid.

In an embodiment of the compound according to the invention, the carbonstereocenter is (R). In another embodiment of the compound according tothe invention, the carbon stereocenter is (S). In yet anotherembodiment, the compound according to the invention is a mixture ofstereoisomers.

In a preferred embodiment of the compound according to the invention, atleast one of R₁, R₂ and R₃ represents C₁-C₃ alkyl. In a more preferredembodiment, at least one, preferably at least two, of R₁, R₂ and R₃represents isopropyl. In another more preferred embodiment, at least oneof R₁, R₂ and R₃ represents methyl. In yet another more preferredembodiment, at least one of R₁, R₂ and R₃ represents ethyl.

In one preferred embodiment of the compound according to the invention,R₁ and R₂ jointly form a ring together with the quaternary ammoniumnitrogen. In a more preferred embodiment, said ring comprises from 4 to6 carbon atoms.

In a preferred embodiment of the compound according to the invention, R₄represents —H, —CH₃, or —CO—R₄₋₁, wherein R₄₋₁ represents C₁-C₄ alkyl.In a more preferred embodiment, R₄ represents —H.

In a preferred embodiment of the compound according to the invention, R₅represents —H, —Br, —Cl, —CH₃, or —CH₂OH, more preferably —CH₃.

In a preferred embodiment of the compound according to the invention, atleast one, more preferably both, of R₆ and R₇ represents —H.

In a preferred embodiment of the compound according to the invention, X⁻is selected from the group consisting of the anions of the followingacids: tartaric, hydrochloric, hydrobromic, hydroiodic, sulfuric,phosphoric, nitric, citric, methanesulfonic, CH₃—(CH₂) —COOH where n is0 thru 4, HOOC—(CH₂)n—COOH where n is 1 thru 4, HOOC—CH═CH—COOH, andbenzoic. In a more preferred embodiment, X⁻ is selected from the groupconsisting of iodide, bromide, and chloride. In an even more preferredembodiment, X⁻ represents iodide. In another even more preferredembodiment, X⁻ represents chloride. In yet another even more preferredembodiment, X⁻ represents bromide.

More specifically, preferred embodiments of the compound according tothe invention include the title compounds of the examples. Particularlypreferred embodiments are selected from the group consisting of

-   -   (3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium        iodide,    -   (3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium        bromide, and    -   (3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium        chloride.

Moreover, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a quaternary ammoniumcompound according to the invention, and a suitable pharmaceuticalcarrier therefor.

The present invention also provides a quaternary ammonium compoundaccording to the invention for use as a medicament.

The present invention provides use of a quaternary ammonium compoundaccording to the invention for the manufacture of a medicament fortreating asthma, chronic obstructive pulmonary disease (COPD), allergicrhinitis, rhinorrhea due to the common cold, or urinary disorder.

Finally, the present invention provides a method of treating asthma,chronic obstructive pulmonary disease (COPD), allergic rhinitis,rhinorrhea due to the common cold, or urinary disorder in a mammal,including man, comprising administering to said mammal, in need of sucha treatment, a therapeutically effective amount of a quaternary ammoniumcompound according to the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 are diagrams showing average enhanced pause (lung resistance)as a function of time upon inhalation of quaternary ammonium saltsaccording to the invention in Balb/c mice.

FIG. 4 is a diagram showing the effects of inhalation of tolterodine anda compound according to the invention, respectively, on the averageenhanced pause (lung resistance) as a function of time in Balb/c mice.

FIG. 5 is a diagram showing the effects of inhalation of a compoundaccording to the invention and ipratropium bromide, respectively, on theaverage enhanced pause (lung resistance) as a function of time in Balb/cmice.

FIG. 6 is a diagram showing the plasma concentration (pg/ml) of acompound according to the invention with time (hours) following aerosoladministration of various amounts in Balb/c mice.

FIG. 7 is a diagram showing the plasma concentration (ng/ml) oftolterodine with time (hours) following aerosol administration ofvarious amounts in mice.

DESCRIPTION OF THE INVENTION

In describing the preferred embodiment, certain terminology will beutilized for the sake of clarity. Such terminology is intended toencompass the recited embodiments, as well as all technical equivalentsthat operate in a similar manner for a similar purpose to achieve asimilar result. To the extent that any pharmaceutically active compoundis disclosed or claimed, it is expressly intended to include all activemetabolites produced in vivo, and, is expressly intended to include allenantiomers, isomers or tautomers where the compound is capable of beingpresent in its enantiomeric, isomeric or tautomeric form.

The compounds of the invention can be prepared by one skilled in the artjust by knowing the chemical structure of the compound to be prepared.The invention is the compounds themselves, not the process chemistry tomake them. The chemistry is known to those skilled in the art.

Accordingly, the compounds of the present invention are quaternaryammonium compounds and are prepared by means, well known to thoseskilled in the art, for preparing quaternary ammonium compounds fromtertiary amines, using the tertiary amines of U.S. Pat. No. 5,382,600and other known compounds as starting materials. The general term“quaternary ammonium compound” relates to any compound that can beregarded as derived from ammonium hydroxide or an ammonium salt byreplacement of all four hydrogen atoms of the NH₄+-ion by organicgroups.

The specific compounds are for nomenclature reasons (see e.g. ChemicalAbstracts) named as “aminium” compounds, but it is possible to use theterm “ammonium” in the names. For example,(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide can also be named as an ammonium compound:(3R)-[3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl)diisopropylmethylammoniumbromide.

More specifically, the invention concerns quaternary ammonium compoundsof the formula:

and any stereoisomers thereof, wherein R₁-R₇ and X⁻ are as follows.

R₁, R₂ and R₃ independently represent C₁-C₆ alkyl, optionallysubstituted with phenyl or hydroxyl, or both, and any two of R₁, R₂ andR₃ may form a ring together with the quaternary ammonium nitrogen.

R₄ represents —H, —CH₃, or —CO—R₄₋₁, wherein R₄₋₁ represents —(C₁-C₄alkyl), —(C₁-C₄ alkoxy), or —NR₄₋₂R₄₋₃, wherein R₄₋₂ and R₄₋₃independently represent —H or —(C₁-C₄ alkyl).

R₅, R₆ and R₇ independently represent —H, —OCH₃, —OH, —CONH₂(carbamoyl), —S0₂NH₂ (sulphamoyl), —F, —Cl, —Br, —I, —CF₃, or —(C₁-C₄alkyl), optionally substituted with one or two —OH, —(C₁-C₄ alkoxy),—COOH, or —CO—O—(C₁-C₃ alkyl), and X⁻ represents an anion of apharmaceutically acceptable acid.

By way of example, a tertiary amine according to U.S. Pat. No.5,382,600, or its salt, is dissolved in a suitable solvent. The tertiaryamine is allowed to react with an organic substrate, e.g. an organichalide.

The substrate contains a C₁-C₆ alkyl, preferably a C₁-C₃ alkyl,optionally substituted with phenyl, and a leaving group. The identity ofthe leaving group is not critical, but it is preferred that the leavinggroup is a halide, such as iodide or bromide. Thus, exemplary substratesinclude methyl iodide, methyl bromide, ethyl iodide, propyl iodide,benzyl bromide or benzyl iodide.

The resulting reaction product is a quaternary ammonium compound, whichis readily crystallized in suitable solvents, known to those skilled inthe art. The crystals thus produced are quaternary ammonium salts. Theiridentity is confirmed by standard methods, such as melting pointdetermination, nuclear magnetic resonance (NMR) analysis and massspectrometry.

The quaternary ammonium compounds of the invention have at least onestereocenter, i.e. the carbon in position 3 (C₃ in the formula below),to which two (substituted) aryl groups are attached optionally, theremay be a second stereocenter (when R₁, R₂ and R₃ all are different), thepositively charged quaternary ammonium nitrogen atom. See the generalformula:

wherein Ar₁and Ar₂ denote (substituted) aryl groups, R₁, R₂, R₃ and X⁻are as above, and C₁, C₂ and C₃ denote individual carbon atoms in thepropylammonium backbone. Accordingly, stereoisomers (enantiomers and/ordiastereomers) are produced. All stereoisomers have useful activity.Therefore, the invention includes use of each stereoisomer separately,as well as mixtures thereof. Specifically, the stereoisomers in whichthe C₃ carbon stereocenter is in the (R) form have useful activity.Moreover, the stereoisomers in which the C₃ carbon stereocenter is inthe (S) form have useful activity. A mixture of stereoisomers,comprising the stereoisomers in which the C₃ carbon stereocenter is inthe (R) form and the stereoisomers in which the C₃ carbon stereocenteris in the (S) form, also has useful activity.

The quaternary ammonium compounds of the invention are preferablyadministered as salts with a pharmaceutically acceptable acid. Where R₄is —H, the compounds can be isolated as internal salts, which have aphenoxide anion to balance the positive charge on the quaternizednitrogen. The preferred pharmaceutically acceptable salts include saltsof the following acids: tartaric, hydrochloric, hydrobromic, hydroiodic,sulfuric, phosphoric, nitric, citric, methanesulfonic,CH₃—(CH₂)_(n)—COOH where n is 0 thru 4, HOOC—(CH₂)_(n)—COOH where n is 1thru 4, HOOC—CH═CH—COOH, and benzoic. For other acceptable salts, seeInt. J. Pharm., 33, 201-217 (1986). Particularly preferred salts arechloride, iodide and bromide salts, especially bromide salts and iodidesalts.

Accordingly, X⁻ represents an anion of a pharmaceutically acceptableacid. Preferably, X⁻ is selected from the following anions: tartrate,chloride, bromide, iodide, sulfate, phosphate(s), nitrate, citrate,methanesulfonate, carboxylates with from two to six carbon atoms,dicarboxylates with from two to six carbon atoms, maleate, fumarate, andbenzoate. It is preferred that X⁻ represents chloride, iodide orbromide, more preferred iodide or bromide.

The substituents R₁, R₂, R₃ may be the same or different. They areselected from the group comprising C₁-C₆ alkyls, preferably C₁-C₅alkyls, straight or branched, optionally substituted with phenyl orhydroxyl, or both. Thus, R₁, R₂, R₃ independently represent methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, orisohexyl, optionally substituted with phenyl or hydroxyl, or both.

It is preferred that at least one of the substituents R₁, R₂, R₃represents a C₁-C₃ alkyl, straight or branched, i.e. methyl, ethyl,propyl, or isopropyl. It is particularly preferred that one of thesubstituents R₁, R₂, R₃ represents methyl or ethyl, preferably methyl.It is also preferred that at least one, more preferred two, of thesubstituents R₁, R₂, R₃ represent(s) isopropyl. It is especiallypreferred that R₁ and R₂ each represent isopropyl, and R₃ representsmethyl or ethyl, preferably methyl. The substituents R₁, R₂, and R₃together contain at least 3 carbon atoms. It is preferred that thesubstituents R₁, R₂, and R₃ together contain at least 4 carbon atoms,more preferred at least 5 carbon atoms, even more preferred at least 6carbon atoms.

According to another aspect of the invention, any two of R₁, R₂, and R₃may jointly form a ring structure together with the positively chargednitrogen. It is preferred that the resulting ring structure comprisesfrom four to six carbon atoms.

The substituent R₄ is attached via an oxygen atom to its aryl ring. The—OR₄ group is attached to the carbon atom in position 2 in the ring,with respect to the propylammonium group. The substituent R₄ mayrepresent hydrogen, methyl or acyl (—CO—R₄₋₁), wherein acyl includes anyone of the following: alkylcarbonyl, straight or branched, having fromtwo to five carbon atoms, alkoxycarbonyl, straight or branched, havingfrom two to five carbon atoms, and amide, optionally mono- orindependently disubstituted with alkyl, straight or branched, havingfrom one to four carbon atom(s). Accordingly, the substituent R₄₋₁represents any one of the following: C₁-C₄ alkyl, straight or branched,C₁-C₄ alkoxy, straight or branched, and —NR₄₋₂R₄₋₃, wherein R₄₋₂ andR₄₋₃ may be the same or different and represent —H or —(C₁-C₄ alkyl),straight or branched. Thus, the substituent R₄ may represent any one ofthe following: hydrogen, methyl or acyl, wherein the acyl group may beacetyl (ethanoyl), propanoyl, butanoyl, isobutanoyl, pentanoyl,isopentanoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, carbamoyl,N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-butylcarbamoyl, or an N,N-dialkylcarbamoyl, wherein the alkyl groups,straight or branched, are the same or different and have from 1 to 4carbon atoms each. Examples of N,N-dialkylcarbamoyls in this positioninclude N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N,N-dipropylcarbamoyl, as well as N,N-diisobutylcarbamoyl, andN-propyl-N-butylcarbamoyl. It is preferred that R₄ represents hydrogen,since such compounds can be isolated as internal salts, which have aphenoxide anion to balance the positive charge on the quaternizednitrogen. It is also preferred that R₄ represents alkylcarbonyl,straight or branched, having from two to five carbon atoms, e.g. acetyl(ethanoyl), propanoyl, butanoyl, isobutanoyl, pentanoyl, orisopentanoyl. Moreover, it is preferred that R₄ represents methyl.

The substituent R₅ may be connected to any, otherwise not substituted,carbon atom in its aryl ring. In other words, R₅ is not connected to anyof the carbon atoms to which the —OR₄ group or the (substituted)phenylpropanammonium group is connected, but R₅ may be connected to anyone of the remaining four carbon atoms in its aryl ring.

R₅ may represent any one of the following: hydrogen, methoxy, hydroxyl,carbamoyl, sulphamoyl, halogen (fluorine, chlorine, bromine, iodine),trifluoromethyl or an alkyl group, straight or branched, having from oneto four carbon atoms. Optionally, this alkyl group may be mono- orindependently disubstituted with hydroxyl, with an alkoxy group,straight or branched, having from one to four carbon atoms, withcarboxyl, or with alkoxycarbonyl (—CO—O—(C₁-C₃ alkyl)), straight orbranched, having from one to four carbon atoms. It is preferred that R₅represents any one of the following: hydrogen, bromine, chlorine, methylor hydroxymethyl. It is particularly preferred that R₅ representsmethyl. If R₅ does not represent hydrogen, it is preferred that R₅ issituated opposite the —OR₄ group, i.e. at the carbon atom in position 5in the ring, with respect to the propylammonium group.

The substituents R₆ and R₇ are connected to the same aryl ring, which isdifferent from the aryl ring to which the substituents R₄ and R₅ areconnected. R₆ and R₇ may be the same or different. R₆ and R₇ mayindependently represent any one of the following: hydrogen, methoxy,hydroxyl, carbamoyl, sulphamoyl, halogen (fluorine, chlorine, bromine,iodine), trifluoromethyl or an alkyl group, straight or branched, havingfrom one to four carbon atoms. Optionally, this alkyl group may be mono-or independently disubstituted with hydroxyl, with an alkoxy group,straight or branched, having from one to four carbon atoms, withcarboxyl, or with alkoxycarbonyl (—CO—O—(C₁-C₃ alkyl)), straight orbranched, having from one to four carbon atoms.

It is preferred that at least one, preferably both, of R₆ and R₇represents hydrogen. When one, but not both, of R₆ and R₇ representshydrogen, it is preferred that the other (R₇ or R₆, respectively) isattached to the carbon atom in position 2 in the ring, with respect tothe propylammonium group. When neither R₆ nor R₇ represent hydrogen, itis preferred that one is attached to the carbon atom in position 2 andthe other to any one of the carbon atoms in positions 3, 4, or 5,respectively, in the ring, with respect to the propylammonium group.

The novel class of compounds according to the present invention areantimuscarinic agents. “Antimuscarinic agents” refer to muscarinicreceptor antagonists. Examples of known antimuscarinic agents includetolterodine, hydroxytolterodine,2-(diisopropylamino)ethyl-1-phenylcyclopentanecarboxylate, propiverine,oxybutynin, trospium, darifenacin, temiverine, ipratropium, andtiotropium.

Propiverine is 1-methyl-4-piperidylalpha.,.alpha-diphenyl-.alpha.-(n-propoxy)acetate and is disclosed inEast German Pat. No. 106,643 and in CAS 82-155841s (1975). Oxybutynin is4-(diethylamino)-2-butynylalphaphenylcyclohexaneglycolate and isdisclosed in UK Pat. No. 940,540. Trospium is3alpha-hydroxyspiro[1alphaH, 5alphaH-nortropane-8,′pyrrolidinium]chloride benzilate and is disclosed in U.S. Pat. No. 3,480,623.Darifenacin is 3-Pyrrolidineacetamide,1-[2-(2,3-dihydro-5-benzofuranyl)ethyl]-alpha,alpha-diphenyl-, and isdisclosed in U.S. Pat. No. 5,096,890. Temiverine is benzeneacetic acid,.alpha.-cyclohexyl-.alpha.-hydroxy-,4-(diethylamino)-1,1-dimethyl-2-butynyl ester and is disclosed in U.S.Pat. No. 5,036,098. Ipratropium is 8-isopropylnoratropine methobromideand is disclosed in U.S. Pat. No. 3,505,337. Tiotropium is(1-alpha,2-beta,4-beta,5-alpha,7-beta)-7-[(hydroxydi-(2-thienyl)acetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonaneand is disclosed in EP 418,716.

The compounds of the invention have anti-cholinergic properties. Thus,they are useful for the treatment of acetylcholine-mediated disorders.In particular, they are useful for treating asthma, chronic obstructivepulmonary disease (COPD), allergic rhinitis, and rhinorrhea due to thecommon cold.

“Asthma” refers to a chronic lung disease causing bronchoconstriction(narrowing of the airways) due to inflammation (swelling) and tighteningof the muscles around the airways. The inflammation also causes anincrease in mucus production, which causes coughing that may continuefor extended periods. Asthma is characterized by recurrent episodes ofbreathlessness, wheezing, coughing, and chest tightness, termedexacerbations. The severity of exacerbations can range from mild to lifethreatening. The exacerbations can be a result of exposure to e.g.respiratory infections, dust, mold, pollen, cold air, exercise, stress,tobacco smoke, and air pollutants.

“COPD” refers to Chronic Obstructive Pulmonary Disease, primarilyassociated with past and present cigarette smoking. It involves airflowobstruction, mainly associated with emphysema and chronic bronchitis.Emphysema causes irreversible lung damage by weakening and breaking theair sacs within the lungs. Chronic Bronchitis is an inflammatorydisease, which increases mucus in the airways and bacterial infectionsin the bronchial tubes, resulting in obstructed airflow.

“Allergic rhinitis” refers to acute rhinitis or nasal rhinitis,including hay fever. It is caused by allergens such as pollen or dust.It may produce sneezing, congestion, runny nose, and itchiness in thenose, throat, eyes, and ears.

“Rhinorrhea due to the common cold” refers to watery discharge from thenose in association with a virus infection, such as the common cold. Therhinorrhea may be caused by rhinitis due to a virus infection (such asthe common cold).

“Urinary disorders” and symptoms thereof include some or all of thefollowing: urgency, frequency, incontinence, urine leakage, enuresis,dysuria, hesitancy, and difficulty of emptying bladder. In particular,urinary disorders include urinary incontinence, caused by e.g. unstableor overactive urinary bladder.

Overactive urinary bladder encompasses variants of urinary disorders,including overactive detrusor (detrusor instability, detrusorhyperreflexia) and sensory urgency, as well as symptoms of detrusoroveractivity, e.g. urge incontinence, urgency, urinary frequency, andLUTS (Lower Urinary Tract Symptoms), including obstructive urinarysymptoms, such as slow urination, dribbling at the end of urination,inability to urinate and/or the need to strain to urinate at anacceptable rate, or irritating symptoms such as frequency, dryoveractive bladder, and/or urgency).

Other conditions are also included, which give rise to urinaryfrequency, urgency and/or urge incontinence. Overactive bladderdisorders also include nocturia and mixed incontinence. While overactivebladder is often associated with detrusor muscle instability, disordersof bladder function may also be due to neuropathy of the central nervoussystem (detrusor hyperreflexia), including spinal cord and brainlesions, such as multiple sclerosis and stroke. Overactive bladdersymptoms may also result from, for example, male bladder outletobstruction (usually due to prostatic hypertrophy), interstitialcystitis, local edema and irritation due to focal bladder cancer,radiation cystitis due to radiotherapy to the pelvis, and cystitis.

The compounds of the present invention are used to treat mammals,including man and horse. It is preferred that the mammal is a human.

The compounds according to the invention, in the form of free base orsalts with pharmaceutically acceptable acids, or solutions thereof, canbe brought into suitable dosage forms, such as compositions foradministration through the oral, rectal, transdermal, parenteral, nasal,or pulmonary route in accordance with accepted pharmaceuticalprocedures. In particular, the compositions may be administered viainhalation or insufflation. Such pharmaceutical compositions accordingto the invention comprise the compounds according to the invention inassociation with compatible pharmaceutically acceptable carriermaterials, or diluents, as is well known in the art. The carriers may beany inert material, organic or inorganic, suitable for administration,such as: water, gelatin, gum arabicum, lactose, microcrystallinecellulose, starch, sodium starch glycolate, calcium hydrogen phosphate,magnesium stearate, talcum, colloidal silicon dioxide, and the like.Such compositions may also contain other pharmaceutically active agents,and conventional additives such as stabilizers, wetting agents,emulsifiers, flavoring agents, buffers, binders, disintegrants,lubricants, glidants, antiadherents, propellants, and the like.

The novel compounds according to the present invention can beadministered in any suitable way. The compounds according to theinvention can be made up in solid or liquid form, such as tablets,capsules, powders, syrups, elixirs and the like, aerosols, sterilesolutions, suspensions or emulsions, and the like. They areadvantageously administered via inhalation or insufflation. When theadministration form is inhalation or insufflation, the compounds arepreferably in the form of either an aerosol or a powder.

The term “effective amount” refers to a therapeutically effective amountfor treating asthma, chronic obstructive pulmonary disease (COPD),allergic rhinitis, rhinorrhea due to the common cold, or urinarydisorder. The terms “therapy” and “therapeutically” encompass all kindsof treatments, including prophylaxis. In particular, “therapeuticallyeffective” means that it is effective for anti-cholinergic treatment.

The dosage of the specific compound according to the invention will varydepending on its potency, the mode of administration, the age and weightof the patient and the severity of the condition to be treated.

Doses administrated by inhaler, such as a dry powder inhaler (DPI) or ametered-dose inhaler (MDI), are preferably given as one or two puffs,preferably comprising the total daily dose. For a human subject, it ispreferred that the dosage is in the range of from 1 microgram (1 μg) toone milligram (1 mg).

Doses administrated by nebulizer solution are generally higher thandoses administrated by inhaler. For a human subject, it is preferredthat the total dosage given by nebulizer solution is in the range offrom 1 microgram (1 μg) to ten milligrams (10 mg).

Thus, a clinically effective amount of the compounds according to theinvention is from about 1 μg to about 10 mg. It is preferred that theeffective amount is from about 1 μg to about 1 mg, preferably from about0.01 mg to about 1 mg.

The compounds of the invention can be administered from one to fourtimes daily. It is preferable to administer the compounds once or twicedaily, more preferable once daily.

The dosage form for inhalation can be an aerosol. The minimum amount ofan aerosol delivery is about 0.2 ml and the maximum aerosol delivery isabout 5 ml. The concentration of the compounds according to theinvention may vary as long as the total amount of spray delivered iswithin the about 0.2 to about 5 ml amount and it delivers an effectiveamount. It is well known to those skilled in the art that if theconcentration is higher, one gives a smaller dose to deliver the sameeffective amount.

The non-active ingredient or carrier can be just (sterile) water withthe pH adjusted to where the active pharmaceutical agent is verysoluble. It is preferred that the pH be at or near 7. Alternatively andpreferably, the non-active carrier agent should be physiological salinewith the pH adjusted appropriately. Aerosols for inhalation of variouspharmaceutical agents are well known to those skilled in the art,including many aerosols for treating asthma.

Alternatively, the dosage form for inhalation can be a powder. Powdersfor inhalation of various pharmaceutical agents are well known to thoseskilled in the art, including many powders for treating asthma. When thedosage form is a powder, the compounds according to the invention can beadministered in pure form or diluted with an inert carrier. When aninert carrier is used, the compounds according to the invention arecompounded such that the total amount of powder delivered delivers an“effective amount” of the compounds according to the invention. Theactual concentration of the active compound may vary. If theconcentration is lower, then more powder must be delivered; if theconcentration is higher, less total material must be delivered toprovide an effective amount of the active compound according to theinvention.

For treatment of rhinitis, in particular rhinitis due to the commoncold, the compounds according to the invention can advantageously beadministered in combination with steroids, cromoglycates, anddecongestants (alpha agonists). Such combination therapies are useful inthe treatment of rhinorrhea due to the common cold.

The invention will be further illustrated by the following non-limitingexamples and pharmacological tests.

Tolterodine refers to2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol, also knownas N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine, acompound of the formula:

Hydroxytolterodine refers to2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol, acompound of the formula:

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

All temperatures are in degrees Celsius.

Ether refers to diethyl ether.

Physiological saline refers to an 0.9% aqueous sodium chloride solution.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

Example 1

Tolterodine Free Base

Tolterodine tartrate (2.1 g) is mixed with water (45 ml) and toluene(2.5 ml). Sodium carbonate (800 mg) is added to the slurry. Sodiumhydroxide (2.0 N, 1.5 ml) is added. The mixture is extracted three timeswith toluene (3 ml), saving the organic phase. Anhydrous potassiumcarbonate is added to the organic phase dissolve the tolterodinetartate, giving the title compound in solution.

Example 2

(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

To tolterodine free base (from Example 1, 0.5 M, 2.5 ml) in toluene isadded methyl iodide (1 ml). Acetonitrile (5 ml) is added to the mixtureand stirred over night at 20-25° C. The solvent is removed by blowingdry nitrogen. Acetone (1 ml) and hexane (2 ml) are added and the mixtureis filtered at 20-25° C. to give the title compound. Anal Calcd forC₂₃H₃₄INO: C, 59.10; H, 7.33; N, 3.00. Found: C, 59.00; H, 7.44; N,3.00. The identity of the compound has been further verified andcharacterised by NMR analysis, mass spectrometry, and melting pointdetermination.

Example 3(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

A sealed mixture of methyl bromide (100 g) and2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (14 g) inacetone (100 ml) is stirred at 20-25° C. for 4 days. The mixture iscooled to −10° C. and the precipitate is filtered off and washed withether and dried to give the title compound, mp 189-191° C. (dec). AnalCalcd for C₂₃H₃₄BrNO: C, 65.71; H, 8.15; Br, 19.00; N, 3.33. Found: C,65.61; H, 8.34; Br, 19.12; N, 3.32. [α]_(D) (c=1, MeOH) +25° C. ¹H NMR[(CD₃)₂SO] δ1.25, 2.18, 2.48, 2.81, 3.05, 3.89, 4.22, 6.70, 6.83, 7.08,7.19, 7.33, and 9.3.

Example 4(3R)-N-Ethyl-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with ethyl iodide, the title compound isobtained.

Example 5(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenyl-N-propylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with propyl iodide, the title compound isobtained.

Example 6(3R)-N-Benzyl-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with benzyl iodide, the title compound isobtained.

Example 7(3R)-N-(tert-Butyl)-3-(2-hydroxy-5-methylphenyl)-N,N-dimethyl-3-phenylpropan-1-aminiumbromide

Following the general procedure of Example 2 and making non criticalvariations, but starting with methyl bromide and2-{(1R)-3-[tert-butyl(methyl)amino]-1-phenylpropyl}-4-methylphenol, thetitle compound is obtained.

Example 8(3R)-3-[2-Hydroxy-5-(hydroxymethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol,the title compound is obtained. Anal Calcd for C₂₃H₃₄INO₂: C, 57.14: H,7.09; N, 2.90. Found: C, 56.33; H, 7.33; N, 2.76. HRMS Calcd 356.2589.Found: 356.2588. ¹H NMR [(CD₃)₂SO] δ1.25, 2.48, 2.81, 3.05, 3.88, 4.26,4.35, 4.94, 6.75, 6.98, 7.20, 7.33, and 9.5.

Example 9(3R)-3-(2-Hydroxyphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

Following the general procedure of Example 3 and making non criticalvariations but starting with2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol, the title compoundis obtained.

Example 10(3S)-3-(2-hydroxyphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

Following the general procedure of Example 3 and making non criticalvariations, but starting with2-[(1S)-3-(diisopropylamino)-1-phenylpropyl]phenol, the title compoundis obtained.

Example 11(3R)-3-(5-Chloro-2-hydroxyphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

Following the general procedure of Example 3 and making non criticalvariations, but starting with4-chloro-2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol, the titlecompound is obtained.

Example 12(3R)-3-(5-Bromo-2-hydroxyphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

Following the general procedure of Example 3 and making non criticalvariations, but starting with4-bromo-2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol, the titlecompound is obtained.

Example 13(3R)-3-[2-(Acetyloxy)-5-methylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

(A) 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl acetateA solution of2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (0.9 g) inacetylchloride (20 ml) is stirred at room temperature for 18 h. Theacetyl chloride is evaporated, ether is added, and the precipitate of2-(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl acetatehydrochloride is filtered off; mp 126-130° C. Anal Calcd forC₂₄H₃₃NO2-HC1: C, 71.35; H, 8.48; Cl, 8.78; N, 3.47. Found: C, 71.02; H,8.30; Cl, 8.64; N, 3.43. [a]D (c=1, MeOH) +110.

The hydrochloride salt is partitioned between ether and saturated sodiumbicarbonate solution. The ether phase is separated and evaporated toobtain the free base of compound (A).

(B)(3R)-3-[2-(acetyloxy)-5-methylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide Following the general procedure of Example 2 and making noncritical variations, but starting with (A):2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl acetate, thetitle compound (B) is obtained.

Example 14(3R)-3-[2-(Isobutyryloxy)-5-methylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl2-methylpropanoate, the title compound is obtained.

Example 15(3R)-3-(4-Fluorophenyl)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methylpropan-1-aminiumbromide

Following the general procedure of Example 3 and making non criticalvariations, but starting with2-[(1R)-3-(diisopropylamino)-1-(4-fluorophenyl)propyl]-4-methylphenol,the title compound is obtained.

Example 16(3R)-3-[2-Hydroxy-5-(trifluoromethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

Following the general procedure of Example 3 and making non criticalvariations, but starting with2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(trifluoromethyl)phenol,the title compound is obtained.

Example 17(3R)-3-[2-(Isobutyryloxy)-5-hydroxymethylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

(3R)-3-[2-hydroxy-5-(hydroxymethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide is acylated with isobutyryl bromide to give the title compound.

Example 18(3R)-3-{2-(Acetyloxy)-5-[(acetyloxy)methyl]phenyl}-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide

(3R)-3-[2-hydroxy-5-(hydroxymethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide is acylated with acetyl bromide, to give the title compound.

Example 19 2-{(1R)-3-[Diisopropyl(methyl)ammonio]-1-phenylpropyl}-4-methylbenzenolate

(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide from Example 2 is passed through an ion exchange column so as toremove the bromide ion and generate the title compound.

Reacting the above compound with an equivalent amount of an acid, suchas methanesulfonic acid, hydrochloric acid, acetic acid, or succinicacid, generates other salts of the title compound.

Example 20(3R)-N,N-Diisopropyl-3-(2-methoxy-5-methylphenyl)-N-methyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with(3R)-N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropan-1-amine,the title compound is obtained; mp 211° C. (dec). Anal Calcd forC₂₄H₃₆INO: C, 59.87; H, 7.54; N, 2.91. Found: C, 59.78; H, 7.56; N,2.99. [α]_(D) (c=1, MeOH) +13°.

Example 21(3R)-3-[2-(Butyryloxy)-5-methylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

(A) 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl butyrate

A solution of2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (1.0 g) inbutyryl chloride (5 ml) is heated under reflux for 90 min. Ether isadded, and the precipitate of2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl butyratehydrochloride is filtered off; mp 116-119° C. Anal Calcd forC₂₆H₃₇NO2.HCl: C, 72.28; H, 8.86; Cl, 8.21; N, 3.24. Found: C, 72.25; H,8.71; Cl, 8.17; N, 3.25. [α]_(D) (c=1, MeOH) +20°.

The hydrochloride salt is partitioned between ether and saturated sodiumbicarbonate solution. The ether phase is separated and evaporated toobtain the free base of the title compound (A).

(B)(3R)-3-[2-(butyryloxy)-5-methylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with (A) :2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl butyrate,the title compound is obtained; mp 175° C. (dec). Anal Calcd forC₂₇H₄₀INO₂: C, 60.33; H, 7.50; N, 2.61. Found: C, 60.37; H, 7.52; N,2.58.

Example 22(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

(3R)-3-[2-(butyryloxy)-5-methylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide (from Example 22) was hydrolysed with methanol, resulting in thetitle compound.

Example 23(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumchloride

A solution of(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide (4.2 g, 0.01 mol) in water (50 ml) is neutralized by addition of1 equivalent of 2 N sodium hydroxide solution (5.0 ml). The solvent isevaporated, and the residual oil is chromatographed to separate2-{(1R)-3-[diisopropyl (methyl)ammonio]-1-phenylpropyl}-4-methylbenzenolate from the sodium bromide.The product is reconstituted in acetone, and a solution of hydrogenchloride in ethyl acetate is added to give a precipitate of the titlecompound.

Example 245-Hydroxy-N-[(3R)-3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl]-N-isopropyl-N-methylpentan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with2-{(1R)-3-[(5-hydroxypentyl)(isopropyl)amino]-1-phenylpropyl}-4-methylphenol,the title compound is obtained.

Example 25(3R)-3-(2-Hydroxy-4-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-5-methylphenol, the titlecompound is obtained.

Example 26

3,3-bis(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with2-[3-(diisopropylamino)-1-(2-hydroxy-5-methylphenyl)propyl]-4-methylphenol,the title compound is obtained.

Example 27(3R)-3-[5-(Aminocarbonyl)-2-hydroxyphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

Following the general procedure of Example 2 and making non criticalvariations, but starting with3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxybenzamide, thetitle compound is obtained.

Example 283,3-bis(2-Methoxyphenyl)-N,N-diisopropyl-N-methylpropan-1-aminium iodide

Following the general procedure of Example 2 and making non criticalvariations, but starting withN,N-diisopropyl-3,3-bis(2-methoxyphenyl)propan-1-amine, the titlecompound is obtained.

Example 29 Large Scale Production of(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide

A 5 l erlenmyer flask was charged with 250 g (526 mmol) tolterodinetartrate, water (2000 ml), and methylene chloride (2000 ml). A solutionof 84 g of 50% NaOH diluted with 200 ml of water was added, and themixture was stirred for 1 hour. The pH was kept in the range of 8-9.Both of the two resulting phases are clear and colorless.

The phases were separated, and the aqueous phase was washed withmethylene chloride (1000 ml). The combined organic phases wereconcentrated on the rotovap (60° C. bath). The weight of the residue wasdetermined. The residue was dissolved in acetone (1000 ml), and 263 ml(2.84 mol) methyl iodide was added, all in one portion. The mixture wasstirred at room temperature overnight.

The resulting slurry was filtered, washed with acetone (250 ml) anddried in the vacuum oven at 50° C. overnight.

This provided 230 g of the desired product,(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide.

Example 30

Cyclic Amine Intermediates

The following general reductive amination procedure was employed:

wherein Ph represents a phenyl group, and R represents an alkyl groupaccording to the following Table I.

Briefly, palladium on activated carbon (1.76 g, 5% by weight, Aldrich20,568-0) was charged to a hydrogenation vessel under nitrogen, followedby a MeOH (20 mL) solution of a racemic lactol(6-methyl-4-phenyl-2-chromanol, see formula above) (4 g, 16.64 mmol) anda secondary amine (42 mmol, 2.5 equiv). The vessel was filled withhydrogen (50 psi), and the reaction mixture was stirred vigorously at50° C. overnight. The heterogeneous reaction mixture was filteredthrough celite. The resulting methanolic solution was concentrated undervacuum.

Pure cyclic amines according to the following table I were obtainedafter trituration with hexanes. TABLE I Intermediate compounds Yield RResulting compound (%) (CH₂)₄ 4-methyl-2-(1-phenyl-3-pyrrolidin-1- 71ylpropyl) phenol (CH₂)₅ 4-methyl-2-(1-phenyl-3-piperidin-1- 33 ylpropyl)phenol (CH₂)₆ 2-(3-azepan-1-yl-1-phenylpropyl)-4- 29 methylphenol

Characterization of 4-methyl-2-(1-phenyl-3-pyrrolidin-1-ylpropyl)phenol:

-   ¹H NMR (CDCl₃): δ1.90 (m, 4H), 2.09 (s, 4H), 2.25-2.45 (m, 2H), 2.57    (m, 2H), 2.63-2.78 (m, 3H), 4.55 (dd, 1H, J=12 Hz, J=3 Hz), 6.47 (s,    1H), 6.85 (s, 2H), 7.19-7.26 (m, 2H), 7.30 (m, 3H), 11.23 (s, 1H).-   ¹³C NMR (CDCl₃): δ19.8, 26.0, 33.5, 39.9, 53.5, 54.3, 125.8, 127.3,    128.1, 128.4, 128.7, 131.2145.0, 153.0.-   ESI mass spectrum: 296 [M+1⁺], 297 [M+2⁺].

Characterization of 4-methyl-2-(1-phenyl-3-piperidin-1-ylpropyl)phenol:

-   ¹H NMR (CDCl₃) : δ1.52-1.53 (m, 2H), 1.62-1.81 (m, 4H), 1.98 (t, 1H,    J=10 Hz), 2.09 (s, 3H), 2.26-2.60 (m, 6H), 4.46 (dd, 1H, J=13 Hz,    J=3 Hz), 6.47 (s, 1H), 6.85 (d, 2H, J=0.9 Hz), 7.19-7.24 (m, 2H),    7.30-7.35 (m, 3H), 11.24 (s, 1H).-   ¹³C NMR (CDCl₃): δ20.9, 24.4, 25.4, 31.3, 38.4, 53.8, 54.7, 61.0,    102.2, 117.9, 126.3, 128.1, 128.4, 128.6, 129.3, 129.4, 131.4,    145.2, 154.3.-   ESI mass spectrum: 310 [M+1⁺], 311 [M+2⁺]

Characterization of 2-(3-azepan-1-yl-1-phenylpropyl)-4-methylphenol:

-   ¹H NMR (CDCl₃): δ1.60-1.65 (m, 4H), 1.65-1.85 (m, 4H), 1.95-2.10 (m,    4H), 2.30-2.67 (m, 6H), 2.70-2.80 (m, 2H).-   ¹³C NMR (CDCl₃) : δ19.6, 26.6, 26.7, 32.0, 40.7, 55.1, 55.7, 115.9,    125.8, 127.3, 128.0, 128.1 128.5, 128.7, 131.4, 145.1, 153.0, 145.2,    152.8.-   ESI mass spectrum: 324 [M+1⁺], 325 [M+2⁺].

Example 311-[3-(2-Hydroxy-5-methylphenyl)-3-phenylpropyl]-1-methylpyrrolidiniumiodide

Methyl iodide (10 equivalents) was added to a solution of the free base4-methyl-2-(1-phenyl-3-pyrrolidin-1-ylpropyl)phenol of Example 30 (0.3g, 1.02 mmol) in acetone (4 mL). The reaction mixture is stirredovernight at room temperature. The solution is concentrated to initiatethe precipitation of the resulting quaternary ammonium salt. The whiteprecipitate is filtered, washed with diethyl ether and dried undervacuum to give a quaternized salt.

White crystals were obtained with a yield of 79%. The resulting compoundwas characterized:

-   ¹H NMR (MeOH-d₄) : δ2.05-2.18 (m, 4H), 2.20 (s, 3H), 2.46-2.62 (m,    2H), 3.08 (s, 3H), 3.14-3.40 (m, 2H), 3.40-3.62 (m, 4H), 4.40 (t,    1H, J=7.3 Hz), 6.68 (d, 1H, J=8Hz), 6.85 (d, 1H, J=8 Hz), 6.98 (d,    1H, J=1.5 Hz), 7.16-7.23 (m, 1H), 7.30 (t, 2H, J=7 Hz), 7.37-7.42    (m, 2H).-   ¹³C NMR (MeOH-d₄) : δ19.3, 21.5, 28.2, 41.5, 46.8, 63.6, 64.5,    115.2, 126.5, 127.9, 128.0, 128.4, 128.5, 128.9, 129.2, 143.4,    152.5.-   Elemental analysis, C₂₁H₂₈INO: Found(%): C 57.64, H 6.43, I 28.77, N    3.23, O 3.88; Theory(%): % C 57.67, H 6.45, I 29.02, N 3.20, O 3.66.-   ESI mass spectrum for C₂₁H₂₈NO+: 310.2.

Example 321-Ethyl-1-[3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl]pyrrolidiniumiodide

Ethyl iodide (10 equivalents) was added to a solution of the free base4-methyl-2-(1-phenyl-3-pyrrolidin-1-ylpropyl)phenol of Example 30 (0.3g, 1.02 mmol) in acetone (4 mL). The reaction mixture is stirredovernight at room temperature. The solution is concentrated to initiatethe precipitation of the resulting quaternary ammonium salt. The whiteprecipitate is filtered, washed with diethyl ether and dried undervacuum to give a quaternized salt.

White crystals were obtained with a yield of 81%. The resulting compoundwas characterized:

-   ¹H NMR (MeOH-d₄): δ1.24 (t, 3H, J=7 Hz), 2.0-2.18 (m, 4H), 2.20 (s,    3H), 2.40-2.63 (m, 2H), 3.08-3.25 (m, 2H), 3.35-3.60 (m, 6H), 4.38    (t, 1H, J=7.5 Hz), 6.70 (d, 1H, J=8 Hz), 6.85 (d, 1H, J=8 Hz), 7.0    (d, 1H, J=1.4 Hz), 7.16-7.23 (m, 1H), 7.30 (t, 2H, J=7 Hz),    7.37-7.42 (m, 2H).-   ¹³C NMR (MeOH-d₄): δ8.0, 19.5, 21.5, 28.0, 41.9, 54.7, 58.0, 64.5,    117.8, 126.4, 127.9, 128.1, 128.4, 128.7, 128.9, 129.2, 143.6,    152.8.-   Elemental analysis, C₂₂H₃₀INO: Found(%) : C 58.17, H 6.65, I 27.79,    N 3.10, O 3.62; Theory(%): C 58.54, H 6.70, I 28.11, N 3.10, O 3.54.-   ESI mass spectrum for C₂₂H₃₀NO+: 324.2.

Example 331-[3-(2-Hydroxy-5-methylphenyl)-3-phenylpropyl]-1-methylpiperidiniumiodide

Methyl iodide (3.42 g, 1.5 mL, 0.024 mol) was added to a solution of thefree base 4-methyl-2-(1-phenyl-3-piperidin-1-ylpropyl)phenol of Example30 (0.3 g, 0.97 mmol) in a mixture of acetonitrile (6 mL) and acetone (2mL). The reaction mixture was stirred overnight at room temperature. Thesolution was concentrated to initiate precipitation of the resultingquaternary ammonium salt. The white precipitate was filtered out, washedwith chloroform and diethyl ether and dried under vacuum to give 0.397 g(90%) of the title compound.

Characterization of the obtained compound:

-   ¹H NMR (MeOH-d₄) : δ1.57-1.84 (m, 6H), 2.19 (s, 3H), 2.46-2.64 (m,    2H), 3.06 (s, 3H), 3.14-3.4 (m, 6H), 4.39 (t, 1H, J=7.3Hz), 6.68 (d,    1H, J=8 Hz), 6.85 (dd, 1H, J=8 Hz, J=1.5 Hz), 7.0 (d, 1H, J=1.5 Hz),    7.18 (t, 1H, J=8Hz), 7.29 (t, 1H, J=7.4 Hz), 7.37-7.4 (m, 5H).-   ¹³C NMR MeOH-d₄): δ19.5, 19.7, 19.8, 20.7, 26.7, 41.5, 60.9, 61.2,    114.0, 115.1, 126.3, 127.9, 128.0, 128.4, 128.5, 128.9, 129.2,    143.4, 152.4.

Example 341-[3-(2-Hydroxy-5-methylphenyl)-3-phenylpropyl]-1-methylazepanium iodide

Methyl iodide (10 equivalents) was added to a solution of the free base2-(3-azepan-1-yl-1-phenylpropyl)-4-methylphenol of Example 30 (0.3 g,1.02 mmol) in CH₂C1₂ (2 mL). The reaction mixture was stirred overnightat room temperature. The solution was concentrated to initiateprecipitation of the resulting quaternary ammonium salt. The whiteprecipitate was filtered out, washed with diethyl ether and dried undervacuum to give a quaternized salt.

White crystals were obtained with a yield of 77%. The resulting compoundwas characterized:

-   ¹H NMR (MeOH-d₄): δ1.6-2.0 (m, 8H), 2.01 (s, 3H), 2.40-2.70 (m,    2H),), 3.10 (s, 3H), 3.15-3.60 (m, 6H), 4.38 (t, 1H, J=7 Hz), 6.68    (d, 1H, J=8Hz), 6.88 (d, 1H, J=8 Hz), 7.05 (s, 1H), 7.18-7.24 (m,    1H), 7.25-7.40 (m, 5H).-   ¹³C NMR (MeOH-d₄): δ20.8, 22.4, 27.5, 41.6, 50.2, 59.2, 63.8, 64.5,    64.8, 117.5, 126.3, 127.95, 128.03, 128.4, 128.6, 128.9, 129.2,    143.4, 152.5.-   ESI mass spectrum for C₂₃H₃₂NO⁺: 338.2.

The usefulness of the compounds according to the invention is furtherillustrated by the following examples.

Example I

Binding Data

Muscarinic receptor subtype M₁-M₅ binding assays were carried out.Briefly, [3]H-methylscopolamine was allowed to bind to membranes fromvarious recombinant mammalian cell lines, each with an over-expressionof a particular receptor subtype. An equilibrium radioliganddisplacement assay was performed using the title compound of example 2,(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide (a quaternary ammonium compound according to the invention), andfor comparison the following anticholinerigic agents: tolterodine,hydroxytolterodine, ipratropium, and atropine. The resulting K_(i)values, displayed in Table II, are averages of duplicate samples at eachdose in an 11-point dose-response curve, using half-log intervals. TABLEII K_(i) values (nM) Displacing compound (3R)-3-(2-Hydroxy-5-methylphenyl)- N,N-diisopropyl-N- methyl-3- Receptor phenylpropan-1-subtype aminium iodide Tolterodine Hydroxytolterodine IpratropiumAtropine M₁ 0.33 0.87 1.5 0.46 0.25 M₂ 0.45 0.73 0.33 0.17 0.43 M₃ 0.202.1 1.4 0.38 0.87 M₄ 0.39 1.5 1.4 0.42 0.48 M₅ 0.25 0.55 0.48 0.54 0.47

Thus, the title compound of example 2,(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide, according to the invention has high affinity and little or noselectivity for any of the muscarinic receptor Ml-M₅ subtypes. ObtainedK_(i) values for(3R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide are in the same range as K_(i) values for tolterodine,hydroxytolterodine, ipratropium, and atropine.

Example II

Bronchodilatory Effect of Inhaled Quaternary Ammonium Salts in Balb/cMice

Female BALB/c mice, weight range 19-22 g, were obtained from CharlesRiver Laboratories (Kingston, N.C.).

They received food and water ad libitum. All procedures in these studieswere in compliance with the Animal Welfare Act Regulation, 9CFR Parts 1and 2, Publication (NIH) 85-23, 1985.

Compounds for aerosol administration were prepared in sterile Dulbecco'sPhosphate Buffered Saline.

Mice were placed in a carousel-style, nose only, exposure chamber andallowed to inhale aerosols for five minutes, using an ICN SPAG-2nebulizer. This nebulizer generates a mean aerosol particle size of 1.3microns at a rate of approximately 0.25 ml/minute.

Ten minutes, 4 hours, 8 hours, 24 hours, 36 hours or 48 hours later, themice were moved to whole body plethysmograph chambers.Bronchoconstriction was induced in mice by administration of an 80 mg/mlmethacholine (MC) aerosol into the plethysmograph chambers for 5minutes. The mice were allowed to inhale an aerosol containing 80 mg/mlmethacholine following inhalation treatment with vehicle, or 80 mg/mlmethacholine following inhalation treatment with 0.072, 0.144, or 1.44mg/ml of the title compound of example 2, i.e.(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide, or 80 mg/ml methacholine following inhalation treatment with1.24 mg/ml ipratropium bromide. The average enhanced pause (lungresistance) was determined. In order to determine the baseline, salineaerosol (without methacholine) was also separately administered to themice.

The results are shown in FIG. 1 (1.44 mg/ml of the title compound ofexample 2 and 1.24 mg/ml ipratropium bromide), FIG. 2 (0.144 mg/ml ofthe title compound of example 2), and FIG. 3 (0.072 mg/ml of the titlecompound of example 2).

Increasing doses of the title compound of example 2 produce increasingdurations of action. In FIG. 1, inhalation of aerosols generated from asolution containing 1.44 mg/ml of the title compound of example 2produced a complete block of methacholine-induced bronchoconstrictionthrough 36 hours following administration. Ipratopium bromide (1.24mg/ml) did not display an equally sustained action. Inhalation ofaerosols generated from solutions containing 0.144 mg/ml (FIG. 2) or0.072 mg/ml (FIG. 3), respectively, of the title compound of example 2prevented methacholine-induced bronchoconstriction through 24 or 8hours, respectively, following administration.

Example III

Bronchodilatory Effect of Inhaled Quaternary Ammonium Salts in Balb/cMice

Female BALB/c mice were obtained and fed as in example II. Compoundswere prepared and administered to the mice (aerosol) as in example II.

Ten minutes, 30 minutes, 1 hour, 2 hours or 4 hours later, the mice wereplaced in plethysmograph chambers, and bronchoconstriction was inducedin the mice by administration of an 80 mg/ml methacholine aerosol. Themice were allowed to inhale an aerosol containing 80 mg/ml methacholinefollowing inhalation with vehicle, or 80 mg/ml methacholine followinginhalation treatment with 1.46 mg/ml tolterodine, or 80 mg/mlmethacholine following inhalation treatment with 1.44 mg/ml of the titlecompound of example 2, i.e.(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide.

The results are shown in FIG. 4. It is obvious from FIG. 4 that thetitle compound of example 2 has a pronounced effect on lung resistance.In addition, the bronchodilatory effects of the title compound ofexample 2 exhibit a prolonged duration.

Example IV

Bronchodilatory Effect of Inhaled Quaternary Ammonium Salts in Balb/cMice

Female BALB/c mice were obtained and fed as in example II. Compoundswere prepared and administered to the mice (aerosol) as in example II.

Ten minutes, 2 hours, 4 hours, 8 hours or 24 hours later, the mice wereplaced in plethysmograph chambers, and bronchoconstriction was inducedin the mice by administration of an 80 mg/ml methacholine aerosol. Themice were allowed to inhale an aerosol containing 80 mg/ml methacholinefollowing inhalation with vehicle, or 80 mg/ml methacholine followinginhalation with 1.44 mg/ml of the title compound of example 2, i.e.(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide, or 80 mg/ml methacholine following inhalation with 1.24 mg/mlipratropium bromide.

The results are shown in FIG. 5. It can be concluded that thebronchodilatory effects of the title compound of example 2 have a longerduration when compared to ipratropium bromide.

Example V

Pharmacokinetics of Inhaled Quaternary Ammonium Salts in Balb/c Mice

Blood samples were taken from the mice in example II via cardiacpuncture under isoflurane anesthesia at 2.5 minutes, 10 minutes, 30minutes, 2 hours, 4 hours, 8 hours, or 12 hours after aerosol drugtreatment.

The samples were collected in tubes containing EDTA and centrifuged at12000×g for four minutes. Plasma was removed and stored at −70° C. untilassay.

Plasma samples were extracted via a liquid/liquid extraction technique.Plasma levels of the title compound of example 2 were determined byESI-LC/MS/MS using a PE SCIEX API 4000 mass spectrometer in positive ionmode. Chromatographically, the analyte and the internal standard wereresolved on a Phenomenex Phenyl-Hexyl column using an isocratic elution.The limit of quantitation was 24 pg/ml.

Plasma concentrations of the title compound of example 2 followingaerosol exposure (inhalation) are summarized in table III and FIG. 6.TABLE III Plasma concentration Plasma concentration ± std dev (pg/ml)following inhalation of various conc. Time 0.072 mg/ml 0.144 mg/ml 1.44mg/ml 2.5 min 136 ± 38 264 ± 21  2675 ± 389 10 min 90 ± 1 162 ± 11  1395± 163 30 min 81 ± 8 112 ± 10 1120 ± 42 2 h 41 ± 6 55 ± 7 245 ± 3 4 h 14± 1 40 ± 3 157 ± 2 8 h — 12 ± 1  80 ± 2 12 h — —  42 ± 2

The doses given to the lungs were proportional to the concentrationsappearing in the plasma. Importantly, the systemic (plasma) exposure wasvery low, which indicates that the title compound of example 2 residesfor a prolonged time in the lung. This correlates well with its longduration of action.

Example VI (Comparative)

Pharmacokinetics of Inhaled Tolterodine in Balb/c Mice

Female BALB/c mice were obtained and fed as in example II. TolterodineL-tartrate for aerosol administration was prepared in sterile phosphatebuffer solution at concentrations of 0.1, 0.5, and 1.0 mg/ml, andadministered to the mice (aerosol) as in example II.

Blood samples were collected at 2.5 minutes, 15 minutes, 30 minutes, 1hour or 2 hours after aerosol drug treatment. Blood samples wereprepared as in example VI. Samples were analyzed using a PE SCIEX API3000 mass spectrometer. Chromatographically, the analyte and theinternal standard were resolved on a Z6rbax ACE Phenyl column using agradient elution. The limit of quantitation was 100 pg/mL.

FIG. 7 shows plasma concentrations of tolterodine following inhalationof nebulized solutions at 0.1, 0.5, or 1.0 mg/ml. Plasma levels for the0.1 mg/ml concentration were at or below detection limits. Clearly,tolterodine is rapidly absorbed into the circulation. The plasma levelof tolterodine is approximately one order of magnitude higher than thecorresponding level of the the title compound of example 2 (example V,FIG. 6).

This demonstrates that while tolterodine is rapidly spread systemically,the compounds according to the invention have an increased duration ofaction, with implications locally (i.e. for treating asthma, chronicobstructive pulmonary disease (COPD), allergic rhinitis, or rhinorrheadue to the common cold).

Example VII

Binding Data

Muscarinic receptor subtype M₁-M₅ binding assays were performed. K_(i)values were determined for the title compounds of examples 3, 8, and31-34 (all quaternary ammonium compounds according to the invention).The resulting K_(i) values are displayed in Table IV. TABLE IV K_(i)values (nM) Receptor Title compound of Example no subtype 3 8 31 32 3334 M₁ 0.3 0.86 1.2 1.1 1.1 1 M₂ 0.52 1.08 2.2 1.7 1.7 1 M₃ 0.43 0.92 3.33.1 3.2 4.7 M₄ 0.72 1.07 4.2 3.8 3.6 2.9 M₅ 0.26 0.68 1.6 1.2 0.9 1.8

Thus, the title compounds of Example nos 3, 8, and 31-34 according tothe invention have high affinity and little or no selectivity for any ofthe muscarinic receptor M₁-M₅ subtypes.

Example VIII

Bronchodilatory Effect of Inhaled Quaternary Ammonium Salts in Balb/cMice

Bronchoconstriction was induced in BALB/c mice by administration ofmethacholine. The title compounds of Examples 3, 8, and 31-34 (allquaternary ammonium compounds according to the invention) wereadministered to the mice via inhalation of 1 mg/mL (free baseequivalents (FBE)) of each compound. The resulting inhibition ofmethacholine-induced bronchoconstriction was determined at 10 min aswell as 24 h and 48 h, or 36 h, after dosing. The results are displayedin the following Table V. TABLE V Title compound % inhibition of ofexample no bronchoconstriction after (1 mg/mL FBE) 10 min 24 h 36 h 48 h3 100 93 8 82 60 15 31 100 0 32 100 17 33 100 0 34 100 0

Example A

A 65 year old female with a history of chronic COPD with FEV₁ of 1.5liters is treated with(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide in an aerosol formulation, 1 mg every 12 hr continuously fordyspnea. After two weeks of therapy, dyspnea tolerance is improved.

Example B

A 50 year old male with a history of chronic COPD with FEV₁/FVC of 60%is treated with(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide in an aerosol formulation, 2 mg every 8 hr continuously fordyspnea. After a week of treatment, the FEV₁/FVC ratio improves to about65%.

Example C

A 25 year old female with a history of asthma with a morning peak flowof less than 2 l/sec is treated with(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide powder, 0.1 mg every 8 hr continuously. Treatment improves thepeak flow to 4-5 l/sec.

Example D

A 35 year old male with a history of severe asthma with a morning peakflow of 5 l/sec is treated with(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumbromide powder, 6 mg once a day continuously. After a week of treatment,the peak flow improves to 9 l/sec.

Example E

A 45 year old female with a history of severe asthma with a morning peakflow of less than 3 l/sec is treated with(3R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminiumiodide in an aerosol formulation, 2 mg three times daily continuously.After a week of treatment the peak flow improves to 6 l/sec.

1-34. (canceled)
 35. The compound2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(trifluoromethyl) phenol.36. A method of forming the compound(3R)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium bromide, comprising reacting methyl bromide and the compound ofclaim 35.